Metabolic syndrome is a modern disease that has rapidly surfaced along with the changes in the living environment in recent years, and various disease groups difficult to control such as type 2 diabetes, arteriosclerotic disease and the like are developed like falling of dominoes. In the series of the disease, what becomes marked together with obesity from the early stage is fatty liver. It has been recently clarified that several dozen percent of patients with fatty liver advance to a disease called non-alcoholic steatohepatitis (NASH). In NASH, a wide range of hepatic parenchyma becomes fibrotic in an alcohol independent manner, and cirrhosis and hepatic cancer are often developed further. While insulin sensitizer, antioxidant, liver supporting agent, anti-hyperlipidemia agent, depressor and the like are used for the treatment of NASH, an established treatment method does not exist, and the development of an effective therapeutic drug has been desired.
The accurate onset mechanism of NASH is still unknown. While a two-hit theory that inflammation and insulin resistance are combined with fatty liver, NASH is developed has been proposed, there is no conclusive experimental proof. As an animal model of NASH, a mouse loaded with MCD (methionine-choline deficient diet) or carbon tetrachloride can be mentioned; however, fibrosis after liver necrosis due to liver failure is the main with decreased body weight, and does not accurately reflect liver fibrosis in human patients with metabolic syndrome, which is caused by obesity and fatty liver due to overnutrition. Once an animal model of NASH capable of reproducing human pathology can be generated, a therapeutic drug for NASH can be screened for or evaluated.
While metabolic syndrome is based on the acquisition of insulin resistance associated with obesity, it has been clarified in recent years that chronic inflammation of adipose tissue is important. Sustained inflammation of adipose tissue due to obesity spreads in the entire body to induce systemic insulin resistance.
The present inventors have clarified in recent years that a key to the pathology is AIM (Apoptosis Inhibitor of Macrophage) as stated below (non-patent documents 1-4). AIM is specifically produced by macrophage and present in blood. Due to obesity, the blood concentration of AIM increases, AIM is incorporated into adipocyte by endocytosis via CD36, induces degradation of accumulated neutral fats (lipolysis), and releases free fatty acid from the adipocyte (non-patent document 5). The released fatty acid induces and maintains chronic inflammation in adipose tissues via stimulation of a toll-like receptor (non-patent document 6). In fact, in AIM knockout (KO) mouse, obesity does not result in chronic inflammation in the entire body including the adipose tissues and the liver, and does not produce insulin resistance, which in turn markedly suppresses the development of diabetes and arteriosclerosis (non-patent documents 4, 6). However, the involvement of AIM in the onset and progression of hepatic diseases, particularly NASH, has not been known heretofore.